Hydrophenanthrene compounds and process of making same



Patented Jan. 10, 1950 HYDROPHENANTHREN'E COIWPOUNDS AND PROCESS OFMAKING SAME Karl Miescher, Riehen, and Jules Heer, Basel, Switzerland,assig'nors to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application September 11, 1947,

Serial No. 773,493. 22, 1946 Switzerland November 6 Claims. (Cl.260-599) It is known that hydrophenanthrene-2-car-' boxylic acids andderivatives thereof having hydrocarbon radicals in the 1- and2-positions are highly active estrogenic compounds.

The present invention is based on the observa tion thathydrophenanthryl-(2)-methanals and hydrophenanthryl-( 2) -methanols,which contain hydrocarbon radicals in the 1- and 2-positions, alsopossess good estrogenic activity. This observation is unexpected becausethe corresponding hydrophenanthrene compounds which contain in the2-position, instead of the carb-oxyl group, an acetyl residue, forexample, are almost physiologically inactive. Thus, the threshold valueof 7-methoxy-2-methyl-l-ethyl-l :2 :3 :4-tetrahydrophenanthryl-(2)-methanal and -(2)- methanol when administeredper s 0r subcutaneously to castrated rats is 0.30.5'y, whereas 7-methoxy2 methyl-1-ethyl-2-acetyl-1:2:3:4- tetrahydrophenanthrene is stillinactive at a value of 900 According to this invention, the newhydrophenanthrene derivatives are made by converting ahydrophenanthrene-2-carboxylic acid which contains hydrocarbon radicalsin the 1- and 2- positions, or a functional derivative of such acid, bymeans of a reducing agent into a hydrophenanthryl- (2) -methanal orhydrophenanthryl- (2)-methanol, and, if desired, converting either ofthe latter compounds into a functional derivative.

The starting materials may contain further substituents. There may beused, more especially, compounds which contain in the '7-position aphenolic hydroxyl group or a substituent 0on thereof are especiallysuitable: 7-hydroxy-, 7-

acyloxyor 'l-alkoxy-l:2-dialkyl-1z2t3z4-tetrahydroor-1:2:3:4:9:10-hexahydroor -1:2:3:- 4:9:11:12-octahydro-phenanthrene-2-carboxylic acids, such as'7-methoxy-2-methyl-1-ethyl- 1:2:3z4 tetrahydrophenanthrene 2 carboxylicacid, 'T-methoXy-Z-methyl-l-ethyl-l :2 3 :4 9 10-.

hexahydrophenanthreneor 7-methoxy-lz2-di methyl-1 :2 :3 4:910-hexahydrophenanthrene-2- carboxylic acid, 7-methoxy-2-methyl-l-ethyl-1:2:3z4: 9:10:11:12 octahydrophenanthrene 2- carboxylic acid,7-hydroxy-1 :2-dimethy1-1 :2 :3 :4

2 tetrahydrophenanthrene-2-carboxylic acid, '7- acetoxy 2 methyl-1-ethyl-1:2z3z4-tetrahydrophenanthrene-2-carboxylic acid, 7-benzoyloxy-1:1: 2 trimethyl 1: 2: 3: 4 tetrahydrophenanthrene2-carboxylic acid,7-methoxy-1z2-dimethyl -1- ethyl -1:2:3:4 tetrahydrophenanthrene-2-carboxylic acid, 2-methyl-1-ethyl-1 :2 :3:4-tetrahydrophenanthrene-2-carboxy1ic acid or functional derivatives ofthese acids.

Most of the starting compounds are known. Insofar as this is not thecase, they may be prepared by known methods [compare K. Miescher andcoworkers, Helv. 2'7, 1727 (1944) 28, 156, 991, 1342, 1506 (1945); 29,586, 1071, 1231, 1889 (1946) Exper. 2, 409 (1946)].

The reduction in the process of the invention may be carried out, moreespecially, by means of catalytically activated or nascent hydrogen.Thus, for example, the acid chlorides may be reduced to the methanals bymeans of hydrogen in the presence of suitable heavy metal catalysts suchas palladium-barium-sulfate, palladiumcharcoal and the like.Furthermore, the corresponding methanols can be obtained directly bythis reaction depending on the conditions used, for example, byprolonging the period of reaction and/0r increasing the reactiontemperature. Again, the thiolic esters, for example, may be convertedinto the methanals or methanols by means of catalysts charged withhydrogen such, for example, as Raney nickel. Thus, for example,reduction with the aid of Raney nickel in aqueous alcohol yieldsmethanals. If on the other hand, the reduction is conducted in absolutealcohol the methanols are obtained as end products. In order to producethe methanols the methanals may subsequently be further reduced by meansof catalytically activated or nascent hydrogen. Methanols, for example,may also be obtained by reacting a carboxylic acid derivative, such asan ester, an acid halide or an acid anhydride with a hydride of a lightmetal or a light metal alloy, such as lithium aluminium hydride.

The aldehydes so obtained may, if desired, be

' converted into-their functional derivatives, such as acetals, .orthioacetals. When the compounds obtained contain substituentsconvertible into phenolic hydroxyl groups these substituents may be soconverted. Thus, an esterified or etherified phenolic hydroxyl group maybe hydrolysed. Compounds containing free alcoholic or phenolic hydroxylgroups may be treated with esterifying or etherifying agents. Thus, forexample, alkyl ethers, such as methyl, ethyl, propyl or butyl ethers, oresters of aliphatic or aromatic acids,

for instance, acetic acid, propionic acid or benzoic acid, may beobtained.

The products of the invention find application as medicaments or asintermediate products.

The invention 1 is i illustrated in the Tollovving examples, in whichthe-parts are by weight-unless otherwise stated and the relationship ofparts by weight to parts by volume is the same as thatiof the gram tothe cubic centimetre:

Example 1 1 part of n-T-methoxy -;2 -;methyl '1 -:ethyl- 122:3:4tetrahydrophenan-threne 2 -carboxylic -thryl- (-2)-=methanal of theformula CHa -orio :isobtained. :Aiter recrystallisation .irom vdilute28432130118 it -;melts rat 92-93 C.

, Asmall iamountiof .the above reaction mixture does not-react with thealdehyde reagents. This aproduct melts (ati56-160" 0.4 and is ,then-'I-.methoxye2+methy1 1-ethyl l :2 13:44 itetrahydrop'heinanthr-yl- Q2-methanol.

:In .an :analogous manner iso-fI-methoxY-iZ- imethyl-rl-ethyl -l-1 2 2 34-tetrahydrophenanthryl- ('2) emethanal {melting at 105-1107 C. obtained-;tetrahydrophenanthrene+21carboxylic-acid.

:Ei'omthesealdehydes .there may be prepared :their afunctionally 1converted derivatives, .such .as the :acetals ior xthioacetals, forvexample, .of the :Eormulae ll and 111 LCH and

carboxylic acid is converted into the acid chloride by means of oxalylchloride. The acid chloride is dissolved in 10 parts by volume oftoluene, and, after the addition of 0.5 part of palladium- 5 {animal*charcoal, i dry hydrogen 'isfintroduced at 100- 110*C. until:hydrogenchlorideiislno longer split off. The reaction solution is then filtered,land the filtrate evaporated under reduced pressure. Thessolidresidue isrecrystallized from di- 2110 ,iliiteemethanol, and the resultingd-l-methoxy- 2-methyl -1-ethyl-1:2:3:4:9 :11: 12-octahydrophenanthrykfimmethanal of Formula IV melts at 858'6 C.

:in :an analogous manner the fl-vmethoxy-2- :methyl-v 1-;eth-yll: 2223.4 5 9. :1 o-rhexahydrophenan :thryl--(2)emethanaliseobtained.

Example "3 ..0.3 part of .n-.'? emethoxye2emethylal-ethy l1:L :'3:14-.tetrahydrophenanthrene 2 -.carboxy1-ic acid methyl thioliciester .ofthe Formula V coson;

(ohtained from the'a'oid-hloride described-inEX- ample 1-viith-the aid'of methyl mercaptan and pyridine) is "heated in 10 'parts by volume ofaqueous alcohol in the presence of 1.5 'parts of Barley-nickel."Thewhol'e' is filtered after a short -time'-to* remove -the catalyst,"the filtrate' is poured *into water, and taken up in ether. After beingwashed and dried, "the ethereal solution "is evapo- "rated, and thealdehyde isisolatedirom the-residue by means ofN-chloro-trimethyl-ammoniumacetic acid hydra-aide. n-7'-methoxy-2-methyl- 1 -e'thyl "1 3 273 :4 tetrahydrophenan'thryl -(2) methanal isobtained by recrystallization from dilute -me'thanol in *the form ofplatelets melting at 92-'9-3-C.

a by-product n '7 methoxy Z-methyl-lethyl "1125314 tetrahydrophenanthryl"(2-) methanol is obtained melting at'56' C. and

/ 60 having the Formula 'VI 0.3 :part of n -"7 -1nethoxy.2-methyl-lethyliEif.-2ri4 -itetrahydrophenanthryl-(2) emethanal f is rhydrqgenatediinthepresence :of a platinum 'catalyst. 'Thehydrogenationisfinishedw'hen-l "mol of hydrogen has been absorbed. The whole isfiltered, and the filtrate is evaporated under reduced pressure. Theresidue is recrystallized from dilute methanol, and, after prolongeddrying, melts at 101-103 C. It is n-7-methoxy-2- methyl 1 ethyl 1222324tetrahydrophenanthryl-(2)-methanol of the Formula VIIa. The acetate (ofFormula VIIb) obtained therefrom melts at 81.5-82.5 0.

-CH2 OR VII VIIB: R=H

In an analogous manner iso-7-methoxy-2- methyl 1 ethyl 122:3:4tetrahydrophenanthryl-(2)-methanol is obtained in an oily form fromiso-7-methoxy-2-methyl-l-ethyl 1:2:3 :4- tetrahydrophenanthryl-(Z)-methanal. The acetate of the former compound melts at 85-86 C.

Example 5 1.3 parts of d-7-methoxy-2-methyl-l-ethyl- 1:2:3:4:9:10:11:12octahydrophenanthryl-(Z)- methanal in 20 parts by volume of methylalcohol are agitated under hydrogen in the presence of 0.2 part ofplatinum oxide. After the absorption of 1 mol of hydrogen thehydrogenation ceases. The reaction solution is then filtered andevaporated, and the residue is recrystallized from pentane. Thed-7-methoxy-2-methyl-1- ethyl-octahydrophenanthryl- (2) -methanol isobtained in the form of dense crystals melting at 71 C. It has thespecific rotation [a] +92.

Example 6 0.3 part of n-7-methoXy-2-methyl-l-ethyl-1:2:3:4-tetrahydrophenanthrene 2 carboxylic acid methyl thiolic ester isboiled in 12 parts by volume of absolute alcohol for 6 hours in thepresence of 3.5 parts of Raney nickel. The whole is filtered, thefiltrate is evaporated, the residue is recrystallized from dilutemethanol, and n-7- methoxy 2 methyl 1 ethyl 1:2:324tetrahydrophenanthryl-(2)-methanol is obtained in the form of lustrousplatelets melting at 56-60" 0., which after prolonged drying undergreatly reduced pressure melt at IOU-103 C.

The starting materials may contain in 'l-position instead of a methoxygroup on other etherified hydroxy group, for example, another alkoxygroup, such as an ethoxy or propoxy group, an esterified hydroxy group,such as an acetoxy, propionyloxy or benzoyloxy group or a free hydroxygroup.

According to the procedure described in Examples 1-6, for example, thefollowing hydrophenanthry1-(2) -methana1s and -methanols can beprepared:

7 acetoxy-1,2-dial1yl-122:3:4 tetrahydrophenanthryl-(2) -methana1 and-methanol.

7 ethoxy-2-methyll-ethyl- 1 :2 :3 :4:910-hexahydrophenanthryl-(2)-methanal and -methanol.

'7-hydroxy-2-methyll-ethyl-1 2 3:4 9:10 11 12- octahydrophenanthryl (2)methanal and -methanol.

7-methoxy-2-benzy1-1-n-propyl- 1:2:3:4 tetra- 6hydrophenanthryl-(2)-methanal and -methanol.

What we claim is:

1. A hydrophenanthrene compound which contains in z-position a member ofthe group consisting of CHO, CH2OH, acetal, thioacetal and CHzOacyIgroups, and. in the 1- and 2-positions hydrocarbon radicals.

2. A hydrophenanthrene compound which contains in 2-positlon a member ofthe group consisting of CHO, CHzOH, acetal, thioacetal and CHzOacylgroups, and in the 1- and Z-positions hydrocarbon radicals and in'l-position a member of the group consisting of a hydroxyl group and asubstituent which on hydrolysis is converted into a hydroxyl group.

3. A 1.2-dialkyl-hydrophenanthrene compound which contains in 2-positiona member of the group consisting of CHO, CHzOH, acetal, thioacetal andCHzOacyl groups, and in 7-position an alkoxy group.

4. The 7-methoxy-2-methyl-1-ethy1-1 2:3:4- tetrahydrophenanthryl (2)methanal of the formula CHO Etc 0- and melting at about 85-86 C.

6. The 'l-methoxy-2-methyll-ethyl-l :2: 3 :4- tetrahydrophenanthryl (2)methanol of the formula H OO and melting at about 56-60 C.

KARL MIESCHER. JULES HEER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Campbell May 25, 1943 OTHER REFERENCESJournal Amer. Chem. Soc., vol. 55, pages 2996-2998 (1933).

Helvetica Chimica Acta, vol. 28, page 992 (1945) Revue Canadienne deBiologie, vol. 3, No. 5,

Number D60. 1944, pages 522-526.

1. A HYDROPHENANTHRENE COMPOUND WHICH CONTAINS IN 2-POSITION A MEMBER OFTHE GROUP CONSISTING OF CHO, CH2OH, ACETAL, THIOACETAL AND CH2O.ACYLGROUPS, AND IN THE 1- AND 2-POSITIONS HYDROCARBON RADICALS.